Tigecycline, (4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-[[[(1,1-dimethylethyl)amino]acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide, is a 9-t-butylglycylamido derivative of minocycline (Merck Index 14th Edition, monograph number 9432, CAS Registry Number 220620-09-7). Compared to other tetracycline antibiotics Tigecycline is more active against tetracycline-resistant strains and also more tolerable. Tigecycline possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline-resistance: ribosomal protection and active efflux of the drug out of the bacterial cell. Furthermore Tigecycline possesses broad spectrum activity, e.g. it is active against gram-positive pathogens (e.g. methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci), gram-negative pathogens (e.g. Acinetobacter baumannii, Stenotrophomonas maltophilia) and anaerobic pathogens. At the moment Tigecycline is indicated for the treatment of complicated skin and soft-tissue infections and intra-abdominal infections. (P. J. Petersen et al., Antimicrob. Agents Chemoth. 1999; 43: 738-744. R. Patel et al., Diagnostic Microbiology and Infectious Disease 2000; 38: 177-179. H. W. Boucher et al., Antimicrob. Agents Chemoth. 44: 2225-2229. D. J. Biedenbach et al., Diagnostic Microbiology and Infectious Disease 2001; 40: 173-177. P. J. Petersen et al., Antimicrob. Agents Chemoth. 2002; 46: 2595-2601. D. Milatovic et al., Antimicrob. Agents Chemoth. 47: 400-404. T. Hirata et al., Antimicrob. Agents Chemoth. 2004; 48: 2179-2184. G. A. Pankey, Journal of Antimicrobial Chemotherapy 2005; 56: 470-480. R. Harris et al., P&T 2006; 31: 18-59).
U.S. Pat. No. 5,675,030 mentions a process for the preparation of Tigecycline hydrochloride by “treating” the free base with hydrochloric acid, but neither an explicit method for the preparation of crystalline Tigecycline hydrochloride, nor the existence of a crystalline form of Tigecycline hydrochloride are described. In Example 9 of said patent an aqueous solution of Tigecycline hydrochloride is lyophilized, whereas, according to U.S. Pat. No. 5,675,030, Tigecycline hydrochloride dihydrate of unknown solid state is obtained. However, repeating the experiment resulted in amorphous Tigecycline hydrochloride.
WO 2005/056538, WO 2006/130418, WO 2006/130431, WO 2006/130500 and WO 2006/130501 disclose Tigecycline, acid addition salts of Tigecycline and processes for the preparation of the same as well. However, in literature no crystalline Tigecycline hydrochloride is described.
Tigecycline is available on the market as lyophilized powder for injection, the originator is Wyeth. During the formulation process Tigecycline is first dissolved in water and then lyophilized. Therefore a crystalline form of Tigecycline or an alternative crystalline acid addition salt of Tigecycline should show high water solubility.
In 2007 the originator launched a novel formulation of Tigecycline in the US. The commercial Tygacil® 2nd generation product contains, according to the originator, following ingredients:
TABLE 1Tygacil ® 2nd generationINGREDIENTQUANTITY PER VIALTigecycline 53 mgLactose monohydrate106 mgHydrochloric acidQ.S. to adjust pHSodium hydroxideQ.S. to adjust pHWater for injectionRemoved during lyophilizationNitrogenQ.S.
The inventors of the present invention surprisingly found that these originator vials contain amorphous Tigecycline hydrochloride instead of the free base, which is due to the addition of hydrochloric acid for pH-adjustment. Therefore it seems to be reasonable to apply crystalline Tigecycline hydrochloride to the lyophilization process instead of the free base, as the salt shows higher water solubility than any crystalline form of the free base.
Moreover the ratio of Tigecycline to hydrochloric acid can be chosen such, that there is no need for pH-adjustment anymore.
Generally, crystalline solids have improved chemical and physical stability over the amorphous form and forms with low crystallinity, therefore crystalline Tigecycline hydrochloride is more preferred than amorphous Tigecycline hydrochloride. Thus there remains a need for crystalline Tigecycline hydrochloride with suitable solubility and stability properties for the formulation of an anti-infective medicament.